Treatment of high-risk neuroblastoma remains one of the greatest challenges for pediatric oncologists. Vincristine (VCR) is effective for the treatment of neuroblastoma. The clinical efficacy of VCR is limited, however, due to its neurotoxic effect, unfavorable pharmacokinetics, and poor drug exposure and delivery to target tissues. Marqibo(r) is the first liposomal formulation of VCR that could improve the pharmacokinetics and toxicity profiles of VCR. However, the lack of pegylation and relatively large size (~150 nm) of Marqibo(r) may result in unfavorable biodistribution and less deeper tumor penetration. Marqibo(r) is only used in clinic to treat adults with a very rare type of leukemia called Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL). The safety and effectiveness of Marqibo(r) in pediatric patients have not been established. It has been reported that smaller nanoparticles such as 30 nm micelles could penetrate poorly permeable tumors for a better anti-tumor effect. The smart VCR loaded micellar nanoparticles (nano-VCR) with smaller size (~16 nm) and on-demand drug releasing properties to be developed in this proposal may offer better efficacy and toxicity profile against neuroblastoma, therefore have great commercial potentials to lead to a marketable VCR-nanoformulation for the treatment of neuroblastoma. The overall goal of this Phase I SBIR proposal is to develop highly effective and less toxic micellar formulation of VCR against neuroblastoma in preclinical animal models, providing validation regarding the feasibility for Phase II studies that will eventually lead to an IND filing to FDA. Our hypotheses are: (i) The smaller crosslinked micelle formulation of VCR (nano-VCR), compared to its free form are more efficacious and less toxic against neuroblastoma; (ii) Fine tuning the level of disulfide crosslinking of nano-VCR will minimize the premature drug release during circulation but allow instant drug release at tumor sites or in tumor cells, therefore will greatly improve the efficacy and toxicity profile; and (iii) N-acetyl cysteine, when administered to the animal 24 hrs after the initial administration of nano-VCR, will further improve its therapeutic index. Nano-VCR will be further decorated with a highly potent ligand to enhance their targeting capability to av3 integrin overexpressed in neovasculatures of neuroblastoma. In this proposal, these hypotheses will be tested in murine neuroblastoma tumor model. The project addresses a critical issue in neuroblastoma therapy to reduce drug toxicity and increase drug efficacy. State of the art design of the nanocarriers via engineering telodendrimers with well-defined structures represents the frontier development of the nanomedicine, in terms of multiple functions, fine-tunable and highly reproducible structure and properties. The use of reversibly crosslinked micelles with fine-tuned stability and on-demand drug releasing property to delivery VCR against neuroblastoma is highly innovative. It's an excellent approach to prevent pre-mature drug release during circulation and deliver high concentrations of drug to tumor site. It is expected that this research will lead to new approach for neuroblastoma therapy.